Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Christel Depienne; Caroline Nava; Boris Keren; Solveig Heide; Agnès Rastetter; Sandrine Passemard; Sandra Chantot-Bastaraud; Marie-Laure Moutard; Pankaj B Agrawal; Grace VanNoy; Joan M Stoler; David J Amor; Thierry Billette de Villemeur; Diane Doummar; Caroline Alby; Valérie Cormier-Daire; Catherine Garel; Pauline Marzin; Sophie Scheidecker; Anne de Saint-Martin; Edouard Hirsch; Christian Korff; Armand Bottani; Laurence Faivre; Alain Verloes; Christine Orzechowski; Lydie Burglen; Bruno Leheup; Joelle Roume; Joris Andrieux; Frenny Sheth; Chaitanya Datar; Michael J Parker; Laurent Pasquier; Sylvie Odent; Sophie Naudion; Marie-Ange Delrue; Cédric Le Caignec; Marie Vincent; Bertrand Isidor; Florence Renaldo; Fiona Stewart; Annick Toutain; Udo Koehler; Birgit Häckl; Celina von Stülpnagel; Gerhard Kluger; Rikke S Møller; Deb Pal; Tord Jonson; DDD Study

doi:10.1007/s00439-017-1772-0

Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Christel Depienne, Caroline Nava, Boris Keren, Solveig Heide, Agnès Rastetter, Sandrine Passemard, Sandra Chantot-Bastaraud, Marie-Laure Moutard, Pankaj B Agrawal, Grace VanNoy, Joan M Stoler, David J Amor, Thierry Billette de Villemeur, Diane Doummar, Caroline Alby, Valérie Cormier-Daire, Catherine Garel, Pauline Marzin, Sophie Scheidecker, Anne de Saint-MartinEdouard Hirsch, Christian Korff, Armand Bottani, Laurence Faivre, Alain Verloes, Christine Orzechowski, Lydie Burglen, Bruno Leheup, Joelle Roume, Joris Andrieux, Frenny Sheth, Chaitanya Datar, Michael J Parker, Laurent Pasquier, Sylvie Odent, Sophie Naudion, Marie-Ange Delrue, Cédric Le Caignec, Marie Vincent, Bertrand Isidor, Florence Renaldo, Fiona Stewart, Annick Toutain, Udo Koehler, Birgit Häckl, Celina von Stülpnagel, Gerhard Kluger, Rikke S Møller, Deb Pal, Tord Jonson, DDD Study

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

70 Citations (Scopus)

Abstract

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

Original language	English
Pages (from-to)	463-479
Number of pages	17
Journal	Human Genetics
Volume	136
Issue number	4
DOIs	https://doi.org/10.1007/s00439-017-1772-0
Publication status	Published - Apr 2017

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Depienne, C., Nava, C., Keren, B., Heide, S., Rastetter, A., Passemard, S., Chantot-Bastaraud, S., Moutard, M.-L., Agrawal, P. B., VanNoy, G., Stoler, J. M., Amor, D. J., Billette de Villemeur, T., Doummar, D., Alby, C., Cormier-Daire, V., Garel, C., Marzin, P., Scheidecker, S., ... DDD Study (2017). Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU. Human Genetics, 136(4), 463-479. https://doi.org/10.1007/s00439-017-1772-0

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title = "Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU",

abstract = "Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.",

author = "Christel Depienne and Caroline Nava and Boris Keren and Solveig Heide and Agn{\`e}s Rastetter and Sandrine Passemard and Sandra Chantot-Bastaraud and Marie-Laure Moutard and Agrawal, {Pankaj B} and Grace VanNoy and Stoler, {Joan M} and Amor, {David J} and {Billette de Villemeur}, Thierry and Diane Doummar and Caroline Alby and Val{\'e}rie Cormier-Daire and Catherine Garel and Pauline Marzin and Sophie Scheidecker and {de Saint-Martin}, Anne and Edouard Hirsch and Christian Korff and Armand Bottani and Laurence Faivre and Alain Verloes and Christine Orzechowski and Lydie Burglen and Bruno Leheup and Joelle Roume and Joris Andrieux and Frenny Sheth and Chaitanya Datar and Parker, {Michael J} and Laurent Pasquier and Sylvie Odent and Sophie Naudion and Marie-Ange Delrue and {Le Caignec}, C{\'e}dric and Marie Vincent and Bertrand Isidor and Florence Renaldo and Fiona Stewart and Annick Toutain and Udo Koehler and Birgit H{\"a}ckl and {von St{\"u}lpnagel}, Celina and Gerhard Kluger and M{\o}ller, {Rikke S} and Deb Pal and Tord Jonson and {DDD Study}",

year = "2017",

month = apr,

doi = "10.1007/s00439-017-1772-0",

language = "English",

volume = "136",

pages = "463--479",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer Nature",

number = "4",

}

Depienne, C, Nava, C, Keren, B, Heide, S, Rastetter, A, Passemard, S, Chantot-Bastaraud, S, Moutard, M-L, Agrawal, PB, VanNoy, G, Stoler, JM, Amor, DJ, Billette de Villemeur, T, Doummar, D, Alby, C, Cormier-Daire, V, Garel, C, Marzin, P, Scheidecker, S, de Saint-Martin, A, Hirsch, E, Korff, C, Bottani, A, Faivre, L, Verloes, A, Orzechowski, C, Burglen, L, Leheup, B, Roume, J, Andrieux, J, Sheth, F, Datar, C, Parker, MJ, Pasquier, L, Odent, S, Naudion, S, Delrue, M-A, Le Caignec, C, Vincent, M, Isidor, B, Renaldo, F, Stewart, F, Toutain, A, Koehler, U, Häckl, B, von Stülpnagel, C, Kluger, G, Møller, RS, Pal, D, Jonson, T & DDD Study 2017, 'Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU', Human Genetics, vol. 136, no. 4, pp. 463-479. https://doi.org/10.1007/s00439-017-1772-0

TY - JOUR

T1 - Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

AU - Depienne, Christel

AU - Nava, Caroline

AU - Keren, Boris

AU - Heide, Solveig

AU - Rastetter, Agnès

AU - Passemard, Sandrine

AU - Chantot-Bastaraud, Sandra

AU - Moutard, Marie-Laure

AU - Agrawal, Pankaj B

AU - VanNoy, Grace

AU - Stoler, Joan M

AU - Amor, David J

AU - Billette de Villemeur, Thierry

AU - Doummar, Diane

AU - Alby, Caroline

AU - Cormier-Daire, Valérie

AU - Garel, Catherine

AU - Marzin, Pauline

AU - Scheidecker, Sophie

AU - de Saint-Martin, Anne

AU - Hirsch, Edouard

AU - Korff, Christian

AU - Bottani, Armand

AU - Faivre, Laurence

AU - Verloes, Alain

AU - Orzechowski, Christine

AU - Burglen, Lydie

AU - Leheup, Bruno

AU - Roume, Joelle

AU - Andrieux, Joris

AU - Sheth, Frenny

AU - Datar, Chaitanya

AU - Parker, Michael J

AU - Pasquier, Laurent

AU - Odent, Sylvie

AU - Naudion, Sophie

AU - Delrue, Marie-Ange

AU - Le Caignec, Cédric

AU - Vincent, Marie

AU - Isidor, Bertrand

AU - Renaldo, Florence

AU - Stewart, Fiona

AU - Toutain, Annick

AU - Koehler, Udo

AU - Häckl, Birgit

AU - von Stülpnagel, Celina

AU - Kluger, Gerhard

AU - Møller, Rikke S

AU - Pal, Deb

AU - Jonson, Tord

AU - DDD Study

PY - 2017/4

Y1 - 2017/4

N2 - Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

AB - Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

U2 - 10.1007/s00439-017-1772-0

DO - 10.1007/s00439-017-1772-0

M3 - Article

C2 - 28283832

SN - 0340-6717

VL - 136

SP - 463

EP - 479

JO - Human Genetics

JF - Human Genetics

IS - 4

ER -

Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

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